Evaluation of NF2 and NF1 Tumor Suppressor Genes in Distinctive Gastrointestinal Nerve Sheath Tumors Traditionally Diagnosed as Benign Schwannomas: A Study of 20 Cases

Abstract

SUMMARY:A significant percentage of conventional schwannomas, whether sporadic or associated with neurofibromatosis 2 (NF2), show loss of heterozygosity (LOH) at NF2 and/or NF2 inactivating mutations. Similarly, a significant percentage of neurofibromas show LOH at NF1 and/or NF1 inactivating mutations. There are no molecular genetic data on gastrointestinal (GI) nerve sheath tumors traditionally diagnosed as benign schwannomas, rare neoplasms possibly derived from the schwannian elements dispersed between the smooth muscle fibers. In this study, we analyzed 1 esophageal, 16 gastric, 1 small intestinal, and 2 colonic tumors of such type. Histologically, all were spindle cell neoplasms positive for S-100 protein, vimentin, and glial fibrillary acidic protein, and negative for smooth muscle markers, KIT, CD34, neurofilament proteins, and HMB45. Focal or extensive lymphoid cuffs, often containing germinal centers, were present in most cases. None of the patients had NF2 or NF1. Chromosomes 22 and 17, particularly NF2 and NF1 loci, were analyzed for LOH in all GI tumors and for comparative purposes in 10 conventional schwannomas. LOH on 22q was seen in 40% of conventional schwannomas but in only 5% (1 of 20) of GI schwannomas. PCR amplification followed by direct sequencing of PCR products failed to identify mutations in NF2 coding sequences (exons 1-15) in 13 cases, including a case with LOH on 22q. Losses on 17q involving NF1 were seen in both GI and conventional schwannomas in 50% and 33% of analyzed tumors, respectively. LOH at NF1 might be one of the genetic features seen in peripheral nerve sheath tumors from different locations and should be interpreted with caution. However, lack of NF2 alterations strongly supports the hypothesis that GI schwannomas represent a morphologically and genetically distinct group of peripheral nerve sheath tumors that are different from conventional schwannomas. (Lab Invest 2003, 83:1361-1371. Distinctive benign nerve sheath tumors traditionally diagnosed as schwannomas have been documented in the gastrointestinal (GI) tract. Their most common location is the stomach, followed by the colon and the rectum. Occasionally, similar tumors have been reported in the small intestine and esophagus. GI schwannomas are cellular spindle cell tumors with a microtrabecular pattern and lack of nuclear palisading. Peripheral lymphoid foci, sometimes with germinal center formation, are a common histologic feature. The tumor cells are positive for S-100 protein and glial fibrillary acidic protein (GFAP) and negative for desmin and ␣-smooth muscle actin (SMA), unlike true leiomyomas, and negative for KIT (CD117) and CD34, unlike GI stromal tumors. All tumors with such phenotypic features reported thus far have followed a benign clinical course (Daimaru et al, 1988;Hirose et al, 1997;Miettinen et al, 2001;Prévot et al, 1999;Sarlomo-Rikala and Miettinen, 1995;Sasatomi et al, 2000;Skopelitou et al, 1998;Tomozawa et al, 1998;Yagihashi et al, 1997).Neurofibromatosis 2 (NF2) is an autosomal dominant diso...

Microsatellite DNA Alterations of Gastrointestinal Stromal Tumors Are Predictive for Outcome

“…A strong association between these LOH and the degree of malignancy (2001 consensus criteria) was observed. This was expected, as several previous studies have shown associations between DNA alterations and GIST malignancy (2,6,17,21,22). As long-term follow-up data were available from our patients, the prognostic role of LOH could also be evaluated in this study.…”

Peripheral nerve sheath tumors of the gastrointestinal tract: a multicenter study of 58 patients including NF1-associated gastric schwannoma and unusual morphologic variants

“…Of interest, intratumoral axons and perineurial cells were detected in GI schwannomas, supporting a neurofibroma-like histogenesis [31]. Moreover, the study by Lasota et al [32] has shown that loss of heterozygosity (LOH) at NF2 was rare in GI schwannomas (5%), and no NF2 mutations could be detected in 13 cases analyzed. Instead, LOH on 17q involving NF1 occurred frequently in GI schwannomas (50%), suggesting a distinct molecular pathogenesis that is more akin to that of plexiform neurofibroma [32].…”

Gastrointestinal stromal tumors: A clinicopathologic and immunohistochemical study of 136 cases

“…Based on the evaluation of NFl and NF2 tumor suppressor genes, GI tract schwannoma is reckoned as an entity differing from the conventional form. 17 Valll, Na 1,2005 In contrast to earlier practice, samples from surgically resected gastrointestinal mesenchymal tumors have been mainly referred to the centers as GISTs or possible GISTs. Naturally, in places where it is not possible to perform ckit immunohistochemistry, or the primary tumor was operated on several years before, other diagnostic possibilities are more often raised.…”